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Clinical Neurology > MED628 - Neuroinflammation and Diseases of the PNS > Flashcards

MED628 - Neuroinflammation and Diseases of the PNS Flashcards

1
Q

Where are interlaminar astrocytes found?

A

in the granular layer of the cerebral cortex of primates, forming a visible palisade

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2
Q

What do perivascular astrocytes form?

A

glial boundaries around blood vessels

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3
Q

What are radial glial remnant cells?

A

transient population of embryonic cells that play an important role in axon guidance, neurogenesis and gliogenesis

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4
Q

What are tanycytes?

A

special ependymal cells found in the third ventricle that extend deep into the hypothalamus, thought to transfer chemical signals from CSF to the CNS.

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5
Q

What are muller cells?

A

radial glial cells of the retina

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6
Q

What do ependymocytes do?

A

contact the ventricular surface and help the flow of CSF with their microvilli

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7
Q

Describe astrocytes role in development

A

o Provide a structural framework for axon guidance (Silver et al, 1993)
o Secrete multiple neurotrophins and cytokines, which promote neuronal differentiation and prevent apoptosis

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8
Q

Describe astrocytes role in synaptic support

A

o Forms the tripartite synapse which helps determine the excitatory signalling the CNS
o Excess glutamate removed by the glutamate reuptake transporter (EAAT2) found exclusively on astrocytes

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9
Q

Describe astrocytes role in energy supply

A

o Glucose transporter (Glut-1) found on astrocytic end feet acts as a gatekeeper for glucose entry into the CNS

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10
Q

Describe astrocytes role in neuroprotection

A

o Have higher concentrations of anti-oxidant molecules (such as vitamin E) than neurons and can protect neurons from oxidative damage
o Secrete glutathione (GSH) which is taken up by surrounding neurons, protecting them from reactive oxygen species and reactive nitrogen species
o In response to oxidative stress, astrocytes increase the activity of the rate limiting enzyme in GSH production, whilst neurons are unable to do this

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11
Q

What is the astrocyte-neuronal lactate shuffle?

A

o Glucose stored as glycogen and transformed into lactate when needed as an alternative energy source by neurons (astrocyte-neuron lactate shuttle)

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12
Q

Describe astrocytes role in synaptic homeostasis

A

o K+ and H+ ions are taken up by astrocytes at the synapse and dissipated through many cells via gap junction coupling

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13
Q

What is the significance of GFAP deficiency in mice given a head trauma?

A
  • GFAP deficient mice suffer greater and delayed neuronal injury in response to blunt head trauma (Liedtke et al, 1996)
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14
Q

What happens if reactive astrogliosis in spinal cord injury is blocked?

A

o Greater neuronal and oligodendrocyte death
o Greater inflammatory infiltration and less recovery of the BBB
o Greater functional deficit
(Faulkner et al, 2004)

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15
Q

How do GFAP knockout mice mature?

A

o GFAP knockout mice mature normally but 50% develop hydrocephalus and white matter loss with impaired BBB function in later life

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16
Q

What happens to astrocytes in ageing?

A

increased astrocytes, especially reactive astrocytes

o Mitochondrial dysfunction results in failure of ATP-dependent processes
o But subpopulations such as fibroblast growth factor-2 positive astrocytes, which promote neurogenesis in the hippocampus, decrease from middle age onwards

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17
Q

Describe microglia

A
  • Not resident cell
  • Normally in repressed state in CNS – constantly surveying environment
  • Role in development
  • Role in adult organism
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18
Q

Describe the double edged sword of activated microglia inflammation

A
  • Injurious/toxic m1 (classically activated) state – Pro-inflammatory cytokine, chemokine, proliferation, phagocytosis, NO release (Nox2)
  • M2 (alternatively-activated) phenotype – Anti-inflammatory-tissue repair and extracellular matrix remodelling, neuroprotective
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19
Q

What happens to microglia as we age?

A
  • Increased activated microglia with age
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20
Q

What are the three populations of microglia in age?

A

o Normal resting microglia
o Hypertrophic microglia
o Dystrophic unhealthy microglia

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21
Q

Describe the natural history of normal myelination in the brain

A
  • ¬Brain is unmyelinated in the newborn
  • Myelination not completed until teens
  • Motor control is poor in newborns
  • Motor development occurs as myelin matures
  • The more maturation of myelin the more complex the motor movement e.g. riding a bike
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22
Q

Name some demyelinating diseases

A
  • Multiple sclerosis
  • ADEM
  • Transverse myelitis
  • Optic neuritis
  • Neuromyelitis Optica
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23
Q

What are some ways of of investigating disease pathophysiology

A
  • Animal models
  • In vitro cell lines
  • Biopsy material from humans
  • Post-mortem studies in humans
  • In vivo
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24
Q

What have studies taught us so far about disease mechanisms in MS?

A
  • Inflammation occurs
  • Axonal damage occurs
  • Recovery occurs too
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25
Q

How does recovery occur in MS?

A

o Resolution of inflammation

o Neuroaxonal redundancy - More nerves than is required

o Remyelination occurs
 Slow and lags behind clinical recovery
 Not always complete

o Neuroplasticity

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26
Q

What are some hypotheses for why some patients fail to recover from MS flairs?

A
  • More severe inflammation?
  • More demyelination?
  • More neuroaxonal loss?
  • More damage elsewhere?
  • Less remyelination?
  • Less tissue reserve? (i.e. less redundancy)
  • Less neuroplasticity?
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27
Q

Name some in vitro research techniques

A
  • Optical coherence tomography (OCT)
    o A measure of axonal damage
  • Optic nerve MRI
    o Gadolinium-enhanced MRI is a measure of inflammation
  • Diffusion-weighted MRI of the optic radiations
    o A measure of tract integrity
  • MRI measurements of cortical thickness and atrophy
    o A measure of neuroaxonal loss
  • Functional MRI
    o A measure of neuroplasticity
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28
Q

What are the key features of MS?

A
  • Inflammatory, demyelinating disease
  • Specific to the central nervous system
  • Commonest cause of chronic neurological disease in young adults
  • Usually begins between ages 20-40 years
  • Early course is relapsing/remitting
  • Progressive disability over time
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29
Q

What are the factors that influence who gets MS?

A
  • Environment
  • Genetics
  • Chance
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30
Q

Describe the epidemiology of MS

A
  • Prevalence lower in regions closer to the equator
    o Prevalence is notably higher in south Australia when compared to the north
  • More common in females than males
    o Ratio of 3:1 for early onset
    o 2:1 for normal range
    o 2.4:1 for late onset
  • More common in white males when compared to black and ‘other’ males
  • Incidence peaks in the 3rd decade of life
    o Bell shaped curve
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31
Q

What can studies of migrants tell us about MS?

A
  • MS prevalence rates can be altered by a change in environment
    o MS is not a purely genetic disease
  • Age at migration is critical for risk retention
    o The potential for developing MS may be established early in life
    o The younger the age of migration the bigger increase risk of developing MS
  • But are migrant populations directly comparable to populations in their native country or the population of their adoptive country?
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32
Q

Name some typical signs of MS

A 
o	Optic neuritis 
o	Spasticity and other pyramidal signs
o	Sensory symptoms and signs
o	Lhermitte’s sign
o	Nystagmus, double vision and vertigo
o	Bladder and sexual dysfunction
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33
Q

Name some atypical signs of MS

A 
o	Aphasia
o	Hemianopia
o	Extrapyramidal movement disturbance
o	Severe muscle wasting
o	Muscle fasciculation
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34
Q

Where can MS plaques occur?

A 
Cerebral hemispheres
Spinal cord
Optic nerves
Medulla and pons
Cerebellar white matter
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35
Q

What are the associated symptoms of MS plaques in the cerebral hemispheres?

A

o Large variety of symptoms such as changes to cognition and motor control
o Also, many silent lesions

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36
Q

What are the associated symptoms of MS plaques in the spinal cord?

A 
o	Weakness 
o	Paraplegia
o	Spasticity 
o	Tingling
o	Numbness
o	Lhermitte’s sign – electric shock like sensation beginning in the neck and radiating to trunk and limbs, can be triggered by tilting head forwards 
o	Bladder and sexual dysfunction
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37
Q

What are the associated symptoms of MS plaques in the Optic nerves?

A

o Impaired vision

o Eye pain

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38
Q

What are the associated symptoms of MS plaques in the Medulla and pons?

A

o Dysarthria
o Double vision
o Vertigo
o Nystagmus

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39
Q

What are the associated symptoms of MS plaques in the cerebellar white matter?

A

o Dysarthria
o Nystagmus
o Intention tremor
o Ataxia

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40
Q

Name the most common presenting symptoms of MS (from most common to least)

A
  • Weakness
  • Paraesthesia
  • Visual loss
  • Incoordination
  • Vertigo
  • Sphincter impairment
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41
Q

Describe relapsing remitting MS

A

o Clearly defined disease relapses with full recovery or with sequelae and residual deficit upon recovery
o Periods between disease relapses characterised by a lack of disease progression

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42
Q

Describe primary progressive MS

A

o Disease progression from onset with occasional plateaus and temporary minor improvements allowed

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43
Q

Describe secondary progressive MS

A

o Initial relapsing-remitting disease course followed by progression with or without occasional relapses, minor remissions and plateaus

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44
Q

Describe progressive/relapsing MS

A

o Progressive disease from onset, with clear acute relapses, with or without full recovery with periods between relapses characterised by continuing progression

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45
Q

What conditions are commonly misdiagnosed as MS?

A
  • Autoimmune disorders such as SLE, Primary Sjogren’s syndrome, Polyarteritis nodosa, ADEM
  • Infectious diseases such as, Lyme disease, Syphilis, AIDS
  • Mitochondrial encephalopathy
  • Arnold-Chiari malformation
  • Cardiac embolic event
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46
Q

Describe the prognosis of MS

A
  • Less than 5-10% of patients will have a clinically milder phenotype with no significant disability
  • More than 30% will develop significant disability within 20-25 years after onset
  • Life expectancy is shortened only slightly
  • Survival rate linked to disability
  • Death usually results from secondary complications (pulmonary or renal)
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47
Q

What is the Marburg variant of MS?

A

acute and clinically fulminant form of the disease that can lead to coma or death within days

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48
Q

What are some clinical indicators of poor prognosis in MS?

A
  • Male gender
  • Late age at onset
  • Early motor, cerebellar, and sphincter symptoms
  • Short inter-attack interval
  • High number of early attacks
  • Early residual disability
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49
Q

What are some paraclinical indicators of poor prognosis in MS?

A
  • Significant MRI disease burden at onset
  • Evidence of MRI disease activity
  • Positive CSF analysis for oligoclonal bands
  • Positive evoked potential exam
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50
Q

Briefly describe the management plan of MS

A 
-	Immunomodulatory therapy for	
o	Acute relapses 
o	Frequent relapses
o	Aggressive illness
o	Progressive illness
  • Management of symptoms
  • Non-pharmacological treatments
    o Physiotherapy
    o Occupational therapy
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51
Q

What is first line treatment for acute relapses in MS?

A
  • Oral or IV methylprednisolone can speed up recovery from a relapse
    o No evidence that this changes the overall disease progression
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52
Q

What can be used short term if steroids cannot be used for acute relapses in MS?

A

Plasmapheresis

o The 2011 AAN guidelines for plasmapheresis states that it is ‘probably effective’ as second-line treatment for relapsing MS exacerbations that do not respond to steroids

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53
Q

How are frequent relapses treated in MS?

A

Disease modifying therapies

  • Shown beneficial effects in patients with relapsing MS inkling reduced frequency and severity of attacks
  • Appear to slow progression of disability and reduce accumulation of lesions within the brain and spinal cord
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54
Q

What are the disease modifying therapies currently approved by the FDA and EMA?

A 
o	Interferon beta-1a (Avonex, Rebif)
o	Interferon beta-1b (Betaseron)
o	Glatiramer (Copaxone)
o	Natalizumab (Tysabri)
o	Mitoxantrone (Novantrone)
o	Fingolimod (Gilenya)
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55
Q

What did the IFNB study group find?

A
  • Double-blind, placebo-controlled study of 372 patients with RRMS (comparing no treatment with interferon beta 1b)

o Decreased frequency of relapses by 34% after 2 years
o In treated patients – MRI T2 lesion burden increased by 3.6% over 5 years, compared to 30.2% in the placebo group
o At 5 year follow up – incidence of disease progression was lower in treatment group

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56
Q

What did the MS collaborative research group study and what were their findings?

A

Studied the efficacy of intramuscular interferon beta 1a

Study of 301 patients
o Annual exacerbation rate decreased by 29%
o Over 2 years, disease progression occurred in 21.9% in treatment group compared to 34.9% of placebo group
o MRI data showed a decrease in mean lesion volume and number of enhancing lesions

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57
Q

What is Glatiramer Acetate?

A
  • Synthetic polypeptide which probably works by substituting itself as the target for the immune system
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58
Q

Describe the evidence for the use of Glatiramer Acetate?

A
  • Double-blind trial of 251 patients with RRMS
    o Resulted in a 29% reduction in relapse rate over 2 years
    o Accumulation of disability was slowed
  • Follow up open-label study
    o Demonstrated efficacy over 6 years
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59
Q

What is natalizumab?

A
  • Humanized monoclonal antibody that binds with the adhesion molecule alpha-4 integrin, inhibiting its adherence to receptors

Second line therapy for MS

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60
Q

Describe the evidence for the treatment of MS with natalizumab

A

Placebo-controlled trial

o Reduced relapse rate (68%) and progression of disability (42%) over 2 years

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61
Q

Why should Natalizumab be used with caution?

A
  • Associated with progressive multifocal leukocephalopathy (PML)
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62
Q

What is Fingolimod and what evidence for its efficacy is there?

A
  • First oral disease modifying treatment
  • Two-year placebo-controlled study
    o Reduced relapse rates by 54-60%, and reduced disability progression by about 30%
  • A one-year study showed that it reduced relapse rates by 53% compared to beta interferon 1a
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63
Q

What are the adverse effects of Fingolimod?

A

o Transient, generally asymptomatic bradycardia
o Atrio-ventricular block with the first dose
o Reduction of lymphocyte count can lead to infection
o Reversible, asymptomatic elevations of liver enzymes
o Headache, diarrhoea, back pain

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64
Q

How should aggressive MS be treated?

A
  • High dose cyclophosphamide
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65
Q

What did a study of 32 patients with aggressive MS show?

A

That those treated with cyclophosphamide followed by long term maintenance with Glatiramer Acetate – well tolerated and appeared to be effective in reducing risk of relapse, disability progression, and new MRI lesions

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66
Q

What are some adverse effects of cyclophosphamide?

A

o Leukaemia
o Lymphoma
o Infections
o Haemorrhagic cystitis

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67
Q

What is an alternative of cyclophosphamide?

A

Mitoxantrone

But
o Risk of cardiotoxicity increasing with every dose
o Risk of leukaemia

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68
Q

What is the treatment of primary progressive MS? What have studies shown?

A
  • Currently no approved treatments
  • Previous trials using a number of DMTs
    o Including interferons, GA, Mitoxantrone, Methotrexate, IVIG, Cyclophosphamide
    o Show no effect on course of the illness
  • On-going trial using Fingolimod
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69
Q

What is Alemtuzumab?

A

Experimental agent for treatment of MS

Monoclonal antibody that targets CD52 cells

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70
Q

What did a phase II trial show for the use Alemtuzumab?

A

Three-year phase II trial of 333 patients with early RRMS
o 71% reduction in disability progression
o 74% reduction in relapse rate

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71
Q

What is the ARE-MS I trial and what did it show?

A

phase III trial comparing Alemtuzumab with Rebif (Interferon beta-1a) in 581 patients
o Alemtuzumab showed 55% reduction in relapse rates
o No significant difference in disease progression

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72
Q

What is the CARE-MS II trial and what did it show?

A

larger phase III study involving 840 people comparing Alemtuzumab to Rebif
o It reduced relapse rates by 49%
o Reduced disability progression by 42%

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73
Q

What is BG12?

A
  • Dimethyl fumarate

- Oral therapy

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74
Q

Describe the DEFINE trial

A

2-year phase III placebo-controlled trial of BG12
o Relapse rates reduced by 53% in twice-daily group, 48% in three-times daily
o Disability progression reduced by 38% and 34%
o MRI scans showed considerable decrease in new or newly enlarging lesions

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75
Q

Describe the CONFIRM trial

A

2-year phase III trial comparing BG-12 with Copaxone (GA)
o Relapse rates reduced by 44% (2x daily) and 51% (3x daily)
o Disability progression reduced by 21% and 24%
o MRI scan showed significant decrease in new or newly enlarging brain lesions

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76
Q

What symptoms of MS should be managed either pharmacologically or non-pharmacologically?

A 
o	Fatigue
o	Spasticity 
o	Bladder problems
o	Bowel problems 
o	Cognitive dysfunction
o	Pain
o	Paroxysmal symptoms 
o	Sexual dysfunction
o	Tremor
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77
Q

Describe the pathogenesis of MS

A
  • Autoreactive lymphocytes become activated in the periphery and migrate to CNS
  • Form accumulations
  • Local inflammatory reaction mediated through inflammatory cytokines, complement and cell cytotoxic mechanisms leading to inflammation, axonal injury and demyelination
  • Patches of inflammation in eloquent areas causes symptoms (e.g. paralysis)
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78
Q

What do MS accumulations contain?

A

o CD8 T cells
o Th17 cells – secrete IL 17 and 22 which disrupts the BBB
o B cells
o Macrophages

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79
Q

What do MS inflammation cause?

A

o Conduction block – lack of saltatory conduction
o Demyelination – most common pathology, stops neuron from working as ion channels only at nodes of Ranvier
o Axonal transection

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80
Q

Describe the clinical history of a MS relapse

A

o Relapse has to be experienced by patient
o May be able to be confirmed by examination
o Must last >48hrs (rules out other pathology such as seizure or TIA)

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81
Q

What are the symptoms and signs of a MS relapse?

A

o Cerebral hemispheres – cognitive changes, visual field loss, hemiplegia
o Optic nerve – visual loss and eye pain (especially on eye movement)
o Brainstem – eye movement disorders, vertigo, ataxia, cranial nerve palsies, hemi-, quadriplegias
o Spinal cord – weakness, bladder, bowel and sexual difficulties

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82
Q

Describe the timescale of a MS relapse

A

o Relapsing remitting
o Days to weeks onset
o Weeks to months recovery
o Not always full recovery especially if had MS for a while
o Most will lead to secondary progressive

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83
Q

What lesions can be seen on MRI of patients with MS?

A
  • Periventricular lesions (adjacent to ventricles) – common pattern
  • Juxtacortical lesions
  • Callosal lesions and Dawson’s fingers (project outwards on the veins into corpus callosum)
  • Posterior fossa and brainstem lesions
  • Temporal lobes lesions
  • Optic nerve lesions (only seen in good scans)
  • Spinal cord lesions
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84
Q

Describe the mcdonald criteria

A

An inflammatory demyelinating disease of the CNS where there is:
o Dissemination in space
o Dissemination in time
o No alternative neurologic disease which may explain the symptoms and signs

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85
Q

Describe the WHO expanded model of illness

A

Organ – pathology
o Disease, diagnosis

Person – impairment
o Observable abnormalities (signs) and subjective experiences (symptoms)

Person in environment – disability/activity limitation
o Inability to perform an activity
o Mobility, communication, activities of daily living

Person in society – handicap/participation
o Inability to fulfils one’s role

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86
Q

Define impairment

A
  • Any loss or abnormality of psychological, physiological, or anatomical structure or function
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87
Q

What are some impairments in MS?

A
  • Loss of vision
  • Dysphagia
  • Ataxia
  • Spasticity
  • Weakness
  • Incontinence
  • Pain
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88
Q

Define disability. What can it affect in MS?

A
  • Any restriction or lack of ability to perform an activity in manner or within the range considered as normal

Can affect

  • Walking
  • Dressing
  • Washing
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89
Q

Define handicap. What main groups can a handicap in MS affect?

A
  • A disadvantage for a given individual resulting from an impairment or disability that limits or prevents the fulfilment of a role that is normal for that individual
  • Unique to each individual and their personal situation E.g. student may have issues with studying and sport

Affects

  • Family
  • Society
  • Vocation
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90
Q

Describe the process of assessment in MS rehab

A
  • Identify the problems
  • Set goals
  • Decide on the setting
  • Interventions
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91
Q

Define spasticity

A

Disordered sensori-motor control resulting from an upper motor neuron lesion, presenting as intermittent or sustained involuntary activation of muscles

o Pandyan et al, Disability and Rehabil 2005

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92
Q

What are the components of spasticity?

A
  • Increased tone
  • Clonus
  • Spasms
  • Spastic dystonia
  • Spastic co-contractions
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93
Q

What are some uses of spasticity?

A 
o	Posture
o	Standing 
o	Walking 
o	Transfers
o	Prevent venous stasis
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94
Q

What are some problems associated with spasticity?

A

o Pain
o Mobility
o Seating
o Hygiene – hand, genital area

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95
Q

What are some non-pharmacological treatments for spasticity?

A

Phsyiotherpay
TENS
Vibration

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96
Q

What are some pharmacological treatments for spasticity?

A

Motor neurons
o GABA – inhibition – Baclofen
o Intrathecal baclofen pump

Inhibitory interneurons
o Alpha-2 agonist – stimulation of interneurons – Tizanidine
o Cannabinoid receptors – Sativex

  • Neuromuscular junction
  • Botox
  • Muscle – Dantrolene (muscle relaxant)
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97
Q

What is spasticity resistant to treatment?

A
  • No response despite use of at least 2 oral anti spasticity drugs in combination
  • No other causes of spasticity such as pressure ulcers, UTI, calculi, any wounds/infections
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98
Q

What are some treatments of spasticity?

A

o Intrathecal baclofen – delivered directly in the subarachnoid space via silicone catheter through anterior abdominal wall
o Phenol – injection
o Alcohol – injection
o Posterior Rhizotomy – severing spinal nerves in neck

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99
Q

What are the treatments for contractures?

A

o Serial casting
o Splints
o Surgery

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100
Q

Describe dropped foot

A
  • Inability to activate ankle dorsiflexors in swing phase of gait
  • Lesion of central neurological origin – corticospinal tracts
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101
Q

What is the treatment of a dropped foot?

A

functional electric stimulation (FES)

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102
Q

What did Taylor et al show in their study of FES?

A

o Retrospective analysis of 23 MS patients in 2016
o Found both external and implanted devices significantly improved walking speed and walking distance
o Indications that walking required less effort
o Improved quality of life
o (Taylor et al, International Journal of MS Care, 2016)

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103
Q

What are potassium channels?

A

inhibitory channels
o Prevent back propagation of action potentials
o Repolarisation

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104
Q

What does Dalfampridine do? Is there evidence for its use?

A

Inhibits potassium channels – better conduction along demyelinated axons

o Review published in 2011
o Randomised, double-blind, placebo-controlled trials
o Walking speed was improved in 1/3 of patients – was 25% above baseline
o (Blight, 2011)

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105
Q

Describe some bladder problems in MS

A
  • Detrusor overactivity – frequency, urgency, incontinence
  • Detrusor areflexia – flaccid, large bladder
  • Detrusor sphincter dyssynergia – incomplete emptying
  • Sphincter over activity – retention, hesitancy
  • Sphincter incompetence – dribbling
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106
Q

How can bladder overactivity be treated?

A
  • Block parasympathetic nerves - Anticholinergic drugs – oxybutynin, fesoterodine
  • Block NMJ – Botox
  • Stimulate sympathetic – Mirabegron – Beta-3 adrenergic receptors
  • Artificial sphincter
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107
Q

How can problems with bladder emptying be treated?

A
  • Tamsulosin – relaxes sphincter

- Catheter

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108
Q

Describe electromyography

A
  • The recording of electrical activity from muscle
  • Disposable needle electrode inserted into the muscle
  • Record from the muscle at the rest
  • Record motor units following voluntary activation
  • Specialised techniques – single fibre EMG
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109
Q

What three things are measured in an EMG?

A

o Motor unit analysis
o Interference pattern
o Spontaneous activity

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110
Q

What are the basic functional elements of the peripheral nervous system?

A

o Anterior horn cell
o Axon
o Neuromuscular junction
o Muscle fibres

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111
Q

Describe the steps in neuromuscular transmission

A
  1. Action potential initiated by motor neuron, travels down myelinated axon via saltatory conduction
  2. Activation of voltage gated calcium channels, influx of Ca2+, Ach release
  3. Ach acts nAchR - influx of Na
  4. Muscle membrane potentials: -90mv to -50mv = threshold for voltage-gated sodium channels
  5. High influx of sodium – at +20mv, sodium channels become inactivated
  6. Increased permeability of the muscle membrane to potassium – K+ leaves, repolarisation of the membrane
  7. The AP across the muscle, release of Ca2+ from sarcoplasmic reticulum
  8. Ca2+ acts with actin and myosin
  9. muscle contraction
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112
Q

What is recorded from the motor unit action potential?

A
  • Amplitude – size
  • Duration
  • Turns – the number of times it changes directions
  • Phases – number of times it crosses the baseline
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113
Q

What is interference pattern?

A
  • Electric activity recorded from the muscle during maximal voluntary effort
  • It is the recruitment of all motor units to the point that no single MUAPs can be distinguished
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114
Q

What should looked for in an interference pattern?

A

Look to see if there is a reduced pattern – where there are areas of baseline with no activity despite maximal effort
o Lose axons – activate fewer motor units
o IP is reduced – you can see gaps in-between the MUAPs

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115
Q

What are the most common spontaneous abnormalities on an EMG?

A

o Fibrillations
o Positive sharp waves
o Fasciculations
o Complex repetitive discharges

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116
Q

What does neurogenic mean?

A

Arising from the nerves - could be traumatic, toxic, metabolic, hereditary

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117
Q

What are fibrillation/positive sharp waves?

A
  • Spontaneous discharge of muscle fibre, always pathological
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118
Q

What do fibrillation/positive sharp waves indicate and why?

A
  • Indicate loss of innervation of muscle fibres (e.g. nerve transection)
  • Deinnervated muscle fibres remain viable but after 7-10 days they become supersensitive
  • Denervated fibres will have acetylcholine receptors over the entire membrane rather than being concentrated at NMJ
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119
Q

What are fasciculations?

A
  • Spontaneous discharge of part or whole of the motor unit
  • Longer and more complex than fibrillations
  • Isolated discharges occurring at irregular intervals
  • May be visible at the skin if near surface
  • May be benign or pathological
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120
Q

Describe complex repetitive discharges

A
  • Start and stop abruptly
  • May persist for several minutes
  • Constant frequency (1-100Hz)
  • Stereotyped group of single fibre potentials with complex morphology
  • Probable ephaptic transmission between adjacent muscle fibres
  • Seen predominantly in neurogenic disease
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121
Q

What are myokymia?

A
  • Regular or irregular discharge of groups of motor units

- Can be seen as flickering in muscle

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122
Q

What is myokymia notably seen in?

A

Seen in central and peripheral pathology

o Notably – brainstem neoplasms or demyelination and sub clinically in episodic ataxia type 1

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123
Q

Describe the timescale of EMG and NCS findings post axonal injury

A

1 day – 2 weeks
o May still have normal/near normal distal NCS (but EMG likely abnormal)
o Poor recruitment on EMG, reduced pattern

3 weeks
o Decreased NCS amplitude or absent (Fibrillations on EMG)

4-6 weeks
o Nascent potentials on EMG

3 months
o Some chronic neurogenic EMG change

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124
Q

What is myopathy?

A

Primary muscle pathology

Damage to and loss of muscle fibres

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125
Q

What changes do you in MUAPs in myopathic disorders?

A
  • Amplitude – reduced
  • Duration - <6ms
  • Phases – increased
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126
Q

What changes do you in the interference pattern in myopathic disorders?

A
  • Full and early

- Low amplitude (the MUAPs are low amplitude)

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127
Q

What is myotonia seen in?

A

muscle fibre membrane channelopathies

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128
Q

Describe single fibre EMGs

A
  • Recording individual muscle fibres
  • Used in diagnosis of NMJ transmission disorders
  • Looking at jitter
  • Blocking seen with more severe disorder
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129
Q

Give an example, other than MNJ transmission disorders, in which single fibre EMG may be abnormal

A

denervation-reinnervation can also result in immature collateral nerve terminals and instability of neuromuscular transmission seen in (for example ALS)

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130
Q

What parts of of the nervous system can NCS assess?

A
  • Anterior horn cell
  • Nerve root
  • Plexus
  • Peripheral nerve
  • Neuromuscular junction
  • (Muscle)
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131
Q

What conditions is NCS used in?

A 
o	MND
o	Polio
o	Radiculopathy
o	Brachial neuritis
o	Peripheral neuropathy 
o	Entrapment neuropathy
o	Myasthenia Gravis
o	Lambert Eaton Syndrome 
o	Polymyositis
o	Muscular dystrophy
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132
Q

What measurements are taken from a NCS?

A 
Latency
Amplitude
Area
Duration of negative phase
Total duration
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133
Q

What common motor nerves are examined in a NCS?

A

o Median
o Ulnar
o Peroneal
o Tibial

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134
Q

What common sensory nerves are examined in a NCS?

A

o Median
o Ulnar
o Radial
o Sural

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135
Q

How do you calculate sensory conduction velocity?

A

CV = Conduction distance/conduction time

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136
Q

What are adult normal values for sensory conduction velocity?

A

o Arm >48m/s

o Leg >38m/s

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137
Q

Why motor conduction velocity more complex? How do you calculate it?

A
  • More complex due to the presences of neuromuscular junctions
  • Need to isolate simply nerve fibres to calculate velocity
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138
Q

What technical considerations are there for NCS?

A

Temperature
o Conduction velocity decreases with decreasing temperature
o Try and warm all patients to 32degrees

Averager
o Taking multiple recordings to cancel out noise as trace stays constant while noise is random

Supramaximal response

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139
Q

What abnormalities are seen in NCS for demyelinating nerve pathology?

A

Slowed CV

Conduction block
 Some fibres do not conduct but not all
 Reduction in area under curve and amplitude together

Dispersion
 Reduction in amplitude but area under curve remains the same
 Some fibres conduct more slowly due to demyelination which spreads the wave out

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140
Q

What abnormalities are seen in NCS for degenerating/axonal nerve pathology?

A

o Reduced amplitude (Normal sensory ≥ 5uV)

o Absent potential

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141
Q

What are F waves? Why do they occur?

A
  • Motor response
  • Second of the two voltage changes seen in nerve conduction studies
  • Occurs after supramaximal stimulation of nerve
    o Stimulation travels in both directions (towards muscle fibre and towards motor cell body)
  • When stimulus reaches cell body and small proportion backfire and stimulus travels back down the neuron seen as the F wave
  • Due to a different population of anterior horn cells stimulated every time, each F wave has a different shape, amplitude and latency
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142
Q

What is repetitive stimulation?

A

Electrical stimulation is delivered to a motor nerve several times a second

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143
Q

What can repetitive stimulation assess?

A
  • By observing changing in electrical response – can assess for pathology of neuromuscular junction and differentiate between presynaptic and postsynaptic conditions
  • Most commonly used to diagnose myasthenia gravis
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144
Q

Name the different types of evoked potentials

A
  • Somatosensory evoked potentials (upper and lower limb)
  • Visual evoked potentials (VEP)/ectroretinography (ERG)
  • Auditory
  • Motor evoked potential (MEP)
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145
Q

What are somatosensory evoked potentials? (SSEPs)

A
  • Responses after electrical stimulation of mixed or cutaneous peripheral nerves
  • Mixed nerves-electrical stimulation sufficient to produce a visible twitch
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146
Q

How electrodes placed in SSEPs?

A

o The 10-20 international systems
o Electrodes are placed at sites that are 10% or 20% of a measured length from a known landmark on the skull
o Same as EEGs

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147
Q

What abnormalities can be seen in SSEPs?

A

o Slowing CV
o Reduced amp or loss of responses
o Asymmetries between sides

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148
Q

What are the uses of SSEPs?

A

Suspect demyelination and myelopathy and can help in
 Distinguishing central and peripheral process
 Prognostication of coma and brainstem death

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149
Q

What would be seen in an SSEP in MS?

A

Asymmetries, prolonged central conduction time, absent responses

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150
Q

What would be seen in an SSEP in spinal cord lesions?

A

markedly prolonged

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151
Q

What would be seen in an SSEP in cortical myoclonus?

A

Giant SSEPs

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152
Q

What does an intact VEP usually suggest?

A

Continuity of the visual pathways

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153
Q

What could an absent VEP indicate?

A

o Technical error (e.g. electrodes in wrong place)
o Poor visual fixation
o Severe optic atrophy

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154
Q

What does a unilateral VEP latency prolongation indicate?

A

slowing of conduction in one optic nerve (optic neuritis)

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155
Q

What does a hemifield prolongation of VEP latency indicate?

A

a conduction defect behind the optic chiasm but

o Specificity and sensitivity not good to confirm posterior lesions

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156
Q

What does a reduced VEP amplitude indicate?

A

ischaemic and compressive disease of the eye and optic nerve

o Amblyopia and glaucoma

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157
Q

What are the 5 waves of Brainstem Auditory Evoked Potentials (BAEPs)?

A

o I – Auditory nerve
o II – Cochlear nuclei – lie at rostral pole of medulla
o III – Superior olivary complex – in pons
o IV – Lateral lemniscus
o V – Inferior colliculus – midbrain

158
Q

What are BAEPs used for in clinical practice?

A

o Screening hearing in infants
o Evaluation of possible acoustic neuroma
o MS
o Evaluate peripheral and central auditory pathways in sedated and anaesthetised patients

159
Q

What are motor evoked potentials used for?

A

Diagnostic use – mainly connection between primary motor cortex and various muscles
o Pathology from MS, CVA, ALS-PLS
o Assess intracortical inhibition etc

160
Q

Name some causes of inflammation

A
  • Infection
    o Bacterial
    o Viral
    o Post -viral
  • Autoimmune
    o MS
    o SLE and connective tissue diseases
  • Ischaemia
  • Neoplasia
161
Q

Name the classical features of inflammation

A 
Celsus (30 BC to 38 AD)
o	Calor – heat
o	Rubor – redness
o	Dolor – pain 
o	Tumor – swelling

Galen (130-200 AD)
o Functio laesa – loss of function

162
Q

What are the classical MR features of inflammation?

A
  • Vascular changes in inflammation - BBB
  • Consequent changes in tissue water content
    o T2 signal, DWI
163
Q

What are the vascular changes in inflammation?

A
  • Increased flow
  • Increased permeability – the BBB
  • Increased inflammatory cell adhesion and recruitment
164
Q

How can increased flow be measured?

A

o Can be measure by perfusion imaging

o	MR perfusion 
	Contrast enhanced
	Arterial spin labelling 
	Indirect: BOLD imaging 
o	CT perfusion – contrast enhanced

o Nuclear medicine

165
Q

What two features are measured in perfusion weighted MR imaging?

A

o Transit time (MTT, or TTP)

o Cerebral blood volume (CBV)

166
Q

What are some classical signs of MS on an MRI scan?

A 
Periventricular predominance 
Corpus callosum involvement 
Temporal lobe involvement 
Posterior fossa involvement 
U-fibre involvement 
Cortical involvement
T1 black hole
Cord lesions - but MR is relatively inconsistent for this
167
Q

Describe a typical MS lesion

A

o Typical lesions are flame shaped

o Fired egg appearance in fresher lesions

168
Q

What are Dawson’s fingers?

A

Ovoid lesions perpendicular to the ventricles

typical for MS and are the result of inflammation around penetrating venules

169
Q

What is essential to look for corpus callosum involvement?

A

o Sagittal FLAIR and/or T2

170
Q

Why is corpus callosum involvement a good differentiating factor for MS?

A

o Not see in leukoaraisosis (Small vessel disease)

171
Q

What part of the posterior fossa is involvement in MS common?

A

Cerebellar peduncle

172
Q

What are U-fibres?

A

o U fibres located right next to cortex, between grey matter and the white matter

173
Q

What are T1 black holes?

A

o Hypointense lesions and indicates the chronic stage with white matter destruction, axonal loss and irreversible clinical outcome

174
Q

ADEM often looks very similar to MS however, what are you more likely to get in ADEM?

A
  • More likely to get large lesions

- More likely to get lesions affecting the basal ganglia/thalamus

175
Q

How may microglial activation be demonstrated?

A
  • Can be demonstrated with iron oxide nanoparticles or Fluorine 19 rich nanoparticles on MR
  • Human studies have been undertaken
  • Can show macrophage recruitment
  • A negative contrast – loss of signal
176
Q

What does the recurrent nerve of Luschka innervate?

A

 Posterior annulus
 Facet joints
 Para vertebral muscles
 Anterior dura

177
Q

What do non-myelinated fibres sense in the spinal cord?

A

 Tissue tension

 Chemical irritants

178
Q

What can cause pain in the spine?

A
  • Distortion in fascial attachments and muscles
  • Muscle fatigue causing local accumulation of metabolites
  • Stress in facet joint and Sacro iliac joint capsules
  • Inflammation of facet joints (OA)
  • Irritation of perivascular and periosteal nerves due to collapse, tumours, fractures and infection
  • Distortion of posterior annulus and PLL by discs
179
Q

Describe the forces on the disc

A
  • Highest when sitting
  • Maximal at lowest end of spine
  • In healthy disc - end plate more likely to rupture than annulus under pressure
180
Q

Describe the ageing of the intervertebral disc

A
  • Dehydration
  • Invasion of fibro cartilage by nucleus
  • Loss of elasticity
  • Fissuring
  • Uniform cartilage plate
  • Caused by decreased blood supply from the end plate
181
Q

What can disc degeneration lead to?

A
  • In ageing disc dehydration and fissuring cause annulus to give way
  • Annulus rupture can occur in any direction by only symptomatic if posterior
182
Q

When is the peak incidence of acute disc disease?

A

Peak incidence of acute disc disease in early middle age

o High level of activity and early degenerative changes

183
Q

What is spondylosis?

A

Chronic disc disease
Occurs later in life
Disc flattening and dehydration

184
Q

What are the secondary changes that occur in chronic disease disease?

A

o OA of facet joints
o Osteophytes
o Ligamentous thickening
o Deformity – spondylolisthesis

185
Q

Describe the incidence of spondylosis

A
  • 4,253 cadavers
  • 50-year olds
    o 69% of women and 80% of men
  • 70-year olds
    o 95% of men
  • Gross changes even in those with no complaints

(Schmorl 1929)

186
Q

Describe cervical cord radiculopathy

A

o Nerve root
o Common
o Self-limiting
o Not recurrent

187
Q

Describe cervical spin myelopathy

A 
o	Spinal cord
o	Often stabilises
o	Some milder cases spontaneously improve
o	Not fully explained by compression 
	Vascular, congenital, ligamentous?
188
Q

What are the clinical features of cervical radiculopathy?

A
  • Neck pain and stiffness
  • Headaches
  • Limb
    o Pain and paraesthesia
    o Sensory loss
    o Weakness
    o Reflex loss
189
Q

What are the clinical features of cervical myelopathy?

A
  • Slow onset or sudden with trauma
  • Upper limbs
    o Numb and clumsy
    o Muscle wasting
  • Lower limbs
    o Stiff heavy legs
    o Poor balance and falls
190
Q

What are some differentials of cervical spinal radiculopathy?

A
  • Carpal tunnel syndrome
  • Ulnar nerve palsy
  • Thoracic outlet syndrome
  • Shoulder girdle problems
  • Brachial neuritis
191
Q

What investigations would you perform for suspected spondylosis?

A 
X-ray 
o	AP
o	Lateral 
o	Oblique 
o	Flexion-extension canal dimensions

MRI
o Good resolution of soft tissue
o High cord signal in T2 weighted image correlates to myelopathy and poor outcome

CT/myelogram
o Bony detail
o Cord and roots seen

EMG/NCS
o To exclude double crush (compression at 2 more locations on a peripheral nerve)
o E.g. nerve root and carpal tunnel

192
Q

What is the conservative management of spondylosis?

A

o Analgesia
o Physiotherapy – avoid manipulation of the neck
o Collar – for 4-6 weeks

193
Q

What is the surgical management of spondylosis?

A

o Decompress cord/roots and remove osteophytes

o Anterior/posterior approach depending on where compression is

194
Q

What results can be achieved following surgery for radiculopahty and for myelopathy?

A

o Radiculopathy – relieved in 80%

o Myelopathy – improved in 60% (complete resolution unlikely)

195
Q

What are some implications for surgery of spondylosis?

A
  • Intractable pain
  • Progressive neurodefecit
  • Cord/root compression on imaging
  • Failure of conservative treatment
196
Q

What are some complications of spondylosis surgery?

A
  • Haemorrhage, infection, CSF leak
  • Recurrent laryngeal nerve damage
  • Tracheal, oesophageal damage
  • Carotid, vertebral artery damage
  • Root and cord damage – quadriplegic
  • Failed fusion
  • Painful hip wound and thigh
  • Bowel perforation
197
Q

Describe the epidemiology of lumbar spine issues

A
  • Low back pain (50 to 90%) during their lifetime
  • 70% improve in 3 weeks
  • 90% in 2 months
  • 1% continue to have symptoms after 1 year
  • Peak incidence in 3rd and 4th decade of life
  • Nachemson’s review
    o 4.8% male, 2.5% female population beyond 35yrs experience sciatica
198
Q

Name some risk factors for lower back problems

A

Smoking
Pregnancy
Certain professions

199
Q

Name some differential for lumber spine issues

A
  • Congenital
    o Meningeal cyst
    o Tethered cord syndrome
    o Conjoined nerve root
  • Acquired
    o Spinal stenosis
    o Spondylolisthesis
    o Juxtafacet cyst
  • Infectious
    o Discitis
    o Caries spine
  • Neoplastic
    o Spine/spinal cord tumours
200
Q

What diagnostic studies should be performed for lumber spine pathology?

A
  • Plain radiography
  • MRI
  • CT scan
  • Myelography
  • EMG
  • Epidural venography
  • Discography
201
Q

What would you see on a plain radiograph for lumbar spine pathology?

A

o Loss of lordotic curve
o Scoliosis
o Disc space narrowing
o Main reason is to exclude other conditions

202
Q

What are the principles of non-operative treatment for lower back pain?

A

o Protect abnormal disc from strain

o Put the part at rest to encourage healing

203
Q

What is the non-operative treatment for lower back pain?

A
  • Decrease in general activity
  • Non-narcotic analgesics/NSAIDs
  • Muscle relaxant
  • Lumbosacral corset
  • Programme of back exercises
204
Q

What are the indications for surgical treatment for lower back pain?

A
  • Cauda equina syndrome with bladder and bowel deficit
  • Progressive motor deficit
  • Significant neurologic deficit with reduced straight leg raising
  • Failure of adequate conservative treatment
  • Recurrent episodes of sciatica
205
Q

What are surgical options for the lumbar spine?

A
  • Microdiscectomy
  • Fenestration
  • Hemilaminectomy
  • Decompressive laminectomy
206
Q

What are some of the complications following lumbar spine surgery?

A
  • Nerve injury
  • CSF leak
  • Infections
  • Spinal instability
  • Post laminectomy kyphosis
  • Urinary retention
  • Injuries to great vessels/viscera
  • Chronic adhesive arachnoiditis
  • Spasm
  • Failed back surgery syndrome
207
Q

What did the Weber series show for surgical vs medical treatment of the lumbar spine?

A

o At 1 year 92% of surgical patients improved compared to 60% for non-surgical
o However, at 4yrs and 5yrs no significant differences between the 2 groups with 60% improved

208
Q

What did the Hakelius series show for surgical vs medical treatment of the lumbar spine?

A

o Immediate surgical results better
o At 6 months no difference between the groups
o At 7 years patients who did not receive surgery had more episodes of lower back pain and sciatica and more lost time from work

209
Q

What are peripheral nerves?

A

Axons originating from anterior horn cells

210
Q

How can neuropathies be classified?

A
  • By cause
  • Acute vs chronic
  • Symmetrical vs asymmetrical (?multifocal)
  • Sensory vs motor vs mixed
  • Axonal vs demyelination
  • Large fibre vs small fibre
211
Q

What the generic causes of neuropathy?

A
  • Unknown – 30%
  • Endocrine diseases
  • Inflammatory diseases
  • Infective
  • Nutritional
  • Metabolic
  • Genetic
  • Neoplastic and paraneoplastic
  • Toxic and pharmacological agents
212
Q

Name some endocrine diseases that can cause neuropathy

A

Diabetes

Hypothyroidism

213
Q

Name some inflammatory diseases that can cause neuropathy

A 
Guillain-Barre syndrome
SLE
Sjogren's 
Vasculitis
Sarcoidosis
214
Q

Name some infective causes of neuropathy

A

Lyme disease
Leprosy
HIV

215
Q

Name some nutritional causes of neuropathy

A

Vitamin B12, B1, vitamin E, B6 toxicity

216
Q

Name some metabolic causes of neuropathy

A

Porphyria
Copper deficiency
Zinc toxicity

217
Q

Name some genetic causes of neuropathy

A

Charcot-Marie-Tooth disease
Friedreich’s ataxia
Fabry disease

218
Q

Name some neoplastic and paraneoplastic causes of neuropathy

A

POEM disease
MGUS
SSCA

219
Q

Name some toxic and pharmacological agents that may cause neuropathy

A 
Vincristine 
Phenytoin
Amiodarone
Metronidazole
Alcohol 
Statins
220
Q

What are the three distributions of neuropathy?

A
  • Mononeuropathy
  • Mononeuropathy multiplex
  • Polyneuropathy
221
Q

Name some extra neurological symptoms of peripheral neuropathy

A
  • Loss of appetite/Loss of weight
  • Rashes
    o Especially non-blanching
  • Skin discolouration
  • Diarrhoea
  • New autonomic features
    o Bladder dysfunction, erectile dysfunction, dry mouth and eyes, cardiac symptoms
  • Family history
222
Q

What findings on examination may you find in someone with peripheral neuropathy?

A
  • Small muscle wasting
  • Inverted champagne bottle wasting in legs
  • Hammer toes, high arched feet
  • Skeletal abnormalities – short fourth toe (Refsum’s disease)
  • Weakness – usually distal, but can be proximal as well (CIDP, GBS)
  • Reduced reflexes
223
Q

What are some unusual and rare but important pointers to the cause of peripheral neuropathy?

A
  • Angular stomatitis – B12, Folate
  • Glossitis – B12/Folate
  • Dentures/denture cream – Zinc toxicity
  • Mees lines – arsenic poisoning
  • Corkscrew hair – Menkes disease, Vitamin C deficiency
  • Burning/painful neuropathy – Amyloidosis, Alcohol
  • Orange tonsils – Tangiers disease
  • AIDS defining findings – HIV neuropathy
224
Q

What investigations should be performed for suspected peripheral neuropathy?

A
  • FBC – indicates effects of vitamin deficiencies, alcohol, inflammation
  • ESR – Raised in inflammation, infection, neoplastic processes
  • RBC – Raised in DM
  • TFT – hypothyroidism
  • Serum immunoglobulin fixation – MGUS neuropathy, POEMS
  • B12 folate
  • EMG/NCS
225
Q

Name the different types of diabetic peripheral neuropathies

A

Diabetic peripheral neuropathy - most common (75)
o Diabetic autonomic neuropathy
o Cranial neuropathy
o Mononeuritis multiplex
o Mononeuropathy
o Treatment-induced neuropathy in diabetes (TIND)

226
Q

Describe diabetic peripheral neuropathy

A
  • Symmetrical, length dependent sensorimotor
  • Attributable to metabolic and micro vessel alterations
  • Result of chronic hyperglycaemia exposure
227
Q

Describe the management of diabetic peripheral neuropathy

A

o Pain management
 Duloxetine and Pregabalin
 Capsaicin/Lidocaine patches
 Opiates – tramadol/codeine (ideally avoided)

o Exercises – help improved nerve fibre regeneration

o Diabetic foot management

o Falls risk – 3 times more likely to fall

228
Q

What are some causes of multiple mono neuropathies?

A

o Vasculitides
o Connective tissue disorders
o Granulomatous inflammation – Sarcoid
o Diabetes

229
Q

What is the management of vasculitis neuropathy?

A

o Treatment should be as you treat renal involvement
o Cyclophosphamide + IVMP
o Non systemic – less aggressive – Management of the cause

230
Q

Briefly describe Charcot Marie Tooth neuropathy

A

o Slow, over many years
o Length dependent
o Motor or sensory
o Sometimes very little symptoms but signs present

231
Q

When should you refer to a specialist for peripheral neuropathy?

A
  • Acute, subacute in onset
  • Rapidly progressive
  • Severe limitation in function
  • Length independent/asymmetrical
  • Multifocal
  • Motor predominant
  • Associated with dysautonomia
  • Demyelinating
  • Associated paraprotein/MGUS
  • Family history
232
Q

What is the prevalence of peripheral neuropathy in the UK?

A

up to 80 per 1000

233
Q

What is the difference between neuropathy and neuronopathy?

A
  • Neuropathy = disease of axons and myelin, long vulnerable to attack by ischaemia or autoimmunity
  • Neuronopathy = whole cell e.g. neurodegenerative, paraneoplastic
234
Q

What are the sensory symptoms of peripheral neuropathy?

A 
o	Proprioception 
o	Light touch, pressure vibration 
o	Pain
o	Warm
o	Cold
235
Q

What are the motor symptoms of peripheral neuropathy?

A 
o	Weakness 
o	Wasting
o	Fasciculation 
o	Cramps
o	Neuropathic tremor
o	Cranial nerve manifestations e.g. double vision
236
Q

What are the autonomic symptoms of peripheral neuropathy?

A

o Bladder/bowel dysfunction
o Blood pressure dysregulation
o Syncope
o Sexual dysfunction

237
Q

What are some common mononeuropathies in the limbs?

A

o Carpal tunnel syndrome (Median nerve)
o Ulnar neuropathy (entrapment at cubital tunnel)
o Peroneal neuropathy (entrapment at the fibular head)

238
Q

What is compression susceptibility enhanced by?

A

increased by systemic conditions e.g. hypothyroidism, pregnancy, acromegaly, HNPP

239
Q

Describe Bells palsy

A

Idiopathic VII palsy
Common, lifetime risk
Can affect any age, gender
Viral in some cases

240
Q

What is the treatment of bells palsy?

A 
o	Exclude central cause
o	Steroids if presenting >72hrs
o	Treat underlying viral infection 
o	Eye care 
o	Surgery/Botox
241
Q

What is common peroneal nerve palsy often caused by?

A

Often compression/trauma

o Habitual leg crossing, fibular head fracture, knee surgery

242
Q

What are the signs of common peroneal nerve palsy?

A
  • Complete or partial foot drop ± numbness
243
Q

What is the treatment of common peroneal nerve palsy?

A

o Exclude L5 radiculopathy
o Treat underlying cause
o Physiotherapy
o Splints

244
Q

How do you differentiate between a surgical vs medical third nerve palsy?

A

o Parasympathetic fibres on outside of nerve therefore more susceptible to compression
o Autonomic involvement = blown pupil
o Usually needs imaging

245
Q

What are the medical causes of oculomotor palsy?

A

microangiopathic (HTN, T2DM)

246
Q

What are some surgical causes of oculomotor palsy?

A

berry aneurysm of posterior communicating artery (classic), basal skull fracture

247
Q

Describe the pattern on mononeuritis multiplex

A
  • Usually not length dependent or symmetrical

Progressive motor and sensory deficit

Most commonly caused by vasculitis

248
Q

Describe symmetrical polyneuropathies

A
  • Length dependent
    o Longer fibres affected first
  • Initially sensory, but eventually sensorimotor
  • Most common type of neuropathy
  • Mostly talking about large fibre polyneuropathies
  • Small fibre – often idiopathic, investigations may be normal, occasionally autoimmune
249
Q

Define muscular dystrophy

A

A group of muscle diseases that result in increasing weakness and breakdown of skeletal muscles over time

250
Q

Describe the mechanisms of muscular dystrophies

A
  • Loss of structural proteins
  • Defective enzymes
  • Disruption of sarcolemma-repair mechanisms
  • Loss of signalling molecules
  • Noncoding region mutations
  • Defective post translational modifications
251
Q

Describe muscular dystrophies

A
  • Over 30 inherited diseases
  • Causing progressive weakness and wasting of muscles
  • Replacement of muscle tissue with fibrous connective tissue
  • Cardiac involvement, respiratory involvement seen in some
  • CNS tissues not usually affected
252
Q

What is the classification of muscular dystrophies?

A

Historical classification - e.g. Duchenne muscular dystrophy

Clinical phenotype – e.g. facioscapulohumeral dystrophy, dystrophia myotonica

Based on inheritance – AD, AR, X-linked

Underlying genetic cause – e.g. DMD – dystrophinopathy

253
Q

What gene is implicated in Duchenne muscular dystrophy (DMD)?

A
  • X-linked recessive – Xp21
254
Q

Describe the pathophysiology of DMD

A
  • Dystrophin localised at the sarcolemma – dystrophinopathy
  • Dystrophin links the ECM and cytoskeleton of each muscle fibre
  • Absence of dystrophin results not only reduced support in the muscle fibre but also results in excess calcium to penetrate sarcolemma
    o Due to alterations in calcium and signalling pathways – water enters mitochondria which burst
    o Results in a complex cascading process, oxidative stress within the cell damages the sarcolemma eventually causing cell death
255
Q

How do you get Becker phenotype of DMD?

A

o Large deletions, duplications, and point mutations that disrupt the reading frame cause of absence of dystrophin – DMD
o BMD phenotype occurs when dystrophin is produced but abnormal – in frame deletions
o Exceptions to reading frame rule – point mutations in binding areas

BMD is milder than DMD as dystrophin is still present

256
Q

Describe DMD presentation

A 
o	Usually presents with motor delayed milestones
o	Wheelchair by 13 years old 
o	Cardiac involvement (100% after 18)
o	Respiratory involvement 
o	Survival beyond 30 is unusual
257
Q

Describe Becker’s muscular dystrophy

A

o Later onset and ambulant into 20s
o Worse cardiac involvement
o Mean age of death – mid 40s

258
Q

Describe the treatment of DMD

A

o Supportive – MDT approach to promote function and independence
o Scoliosis corrective surgery as children
o Manage cardiac failure and arrythmias – Beta blockers, ACEi, transplantation
o NIV and cough assistance/physio
o Steroids
o Gene therapy – anti sense oligonucleotides weekly s/c injections
o Family support
o Female carriers

259
Q

What are the two different types of myotonic dystrophy?

A
  • DM1 – 1 in 7,400

- DM2 – less common

260
Q

Describe the genetics of myotonic dystrophy

A
  • Most common genetic disease of muscle
  • Autosomal dominant

DMPK (DM1) - Codes for myotonic dystrophy protein kinase
 CTG repeats
 Normally 5-37
 DM1 – Over 50 repeats

ZNF9 (DM2)
 CCTG
 Normally 10-33
 DM2 - usually around 5000 repeats

261
Q

Describe anticipation in myotonic dystrophy

A

o Disease onset younger and more severe in each generation

o CTG is unstable, growing by 200 per generation

262
Q

What is the most common presentation of DM1?

A

Myotonia most common presentation
o Pronounced after rest
o Eases with warm up
o Cranial, trunk and distal muscles

263
Q

Describe muscle wasting and weakness in DM1

A

o Ptosis, wasting of temporalis, masseter, facial weakness
o Tongue weakness
o Long finger flexors and ankle dorsiflexors
o Ocular motility can be affected
o Diaphragm weakness, respiratory failure

264
Q

Describe cardiac symptoms in DM1

A

o Cardiac dysrhythmia 2nd leading cause of death
o Heart block, atrial tachycardias, ventricular tachycardia
o Progressive conduction defects
o Heart failure not uncommon – rare under 40, 30% at 70yrs
o Prospective risk of sudden death 1.1% per year

265
Q

What ocular problem can you get in DM1?

A

Cataracts

266
Q

Describe CNS symptoms in DM1

A

o Sleep disturbance
o Behavioural and cognitive change
o White matter changes on MRI – cause uncertain

267
Q

Describe GI symptoms in DM1

A

o Gall bladder problems

o Intestinal dysmotility
 Urgency
 Diarrhoea
 Constipation

268
Q

What cancers are patients with DM1 more at risk of?

A

o Thyroid, ovary, colon, endometrium, brain, eye

269
Q

Describe hypogonadism in DM1

A

o Testicular atrophy
o Reduced fertility
o Erectile dysfunction

270
Q

What metabolic problems can you get in DM1?

A

o Diabetes, insulin resistance
o High cholesterol and triglycerides
o Abnormal LFTs – no action unless other symptoms
o Balding – men and women

271
Q

Describe the treatment of myotonic dystrophy

A

Myotonia
o Anticonvulsants, mexiletine

Pain
o Analgesic ladder

Monitor
o EEG, Glucose, lipids, cataracts, respiratory failure

Erectile dysfunction

Genetic counselling

272
Q

Briefly describe myasthenia gravis

A
  • Prototypical disease of the neuromuscular junction
  • Antibody-mediated
    o Anti-acetylcholine receptor antibody identified and shown to pathogenic
  • Fatigable weakness
273
Q

Describe the pathophysiology of MG

A
  • Autoantibodies against acetylcholine receptors on post synaptic membrane
    o Produce complement mediated damage and increase the rate of AChR turnover
  • Leads to weakness and fatiguability of skeletal muscle
  • Thymus gland is involved in most patients
  • In a small proportion of patients who lack AChR antibodies, antibodies to muscle specific kinase (MuSK) or related proteins such as agrin can be found
274
Q

How do you prove causality in MG as an antibody-mediated disease?

A
  • Antibodies present at site of pathology (i.e. the NMJ)
  • Antibodies from MG patients cause MG symptoms when injected into rodents
  • Immunisation of animals (i.e. with Ach) reproduces the disease
  • Therapies that remove antibodies ameliorate the disease
275
Q

Describe the epidemiology of MG

A
  • UK – 15 per 100,000
  • Europe – 4.5-10 per 100,000
  • USA – 20 per 100,000
  • Relatively rare
  • More females than males at young age
    o Although more men later in live
    o Biphasic and bimodal curve
276
Q

Describe pure ocular MG

A

o Ptosis
o Diplopia
o Pupil always spared
o Must follow up to ensure it doesn’t progress to generalised MG

277
Q

What crises can occur in MG?

A

o Myasthenic crisis

o Cholinergic crisis

278
Q

What investigations should be undertaken for suspected MG?

A 
Clinical examination 
Antibody tests 
EMG
CT thorax
Tensilon test
279
Q

What should you look for on clinical examination of MG?

A

Muscle fatigue

280
Q

What antibody tests should be ordered for MG?

A

AChR - positive in 80% generalised, 50% ocular

Anti-MuSK - in 7%

No antibodies in 7%

Thyroid - to rule out thyroid conditions

281
Q

What would see on an EMG of an MG patient?

A

o Decrement – train of stimuli (electrophysiological fatigability)
o Single fibre EMG – Jitter (95% sensitive)

282
Q

What are you looking for on a CT thorax of an MG patient?

A

o Look for thymoma (usually benign tumour)

283
Q

What is a tensilon test?

A

Adminsitering edrophonium

o AChE inhibitor
o Can temporarily reverse MG signs
o Administered IV and in a double-blind fashion
o Not done anymore as can cause symptomatic bradycardia

284
Q

What are the treatment principles in MG?

A

o Increase the synaptic cleft acetylcholine concentration
o Avoiding immune mediated end-plate damage
o Removing antibodies and their production

285
Q

Describe first line management of generalised MG?

A

Association of British Neurologist Guidelines 2015: (5)
- Pyridostigmine + Prednisolone (if still symptomatic) acutely

  • Prednisolone at lowest effective dose to maintain remission
  • Alternative immunosuppression only introduced if there is failure to respond to prednisolone, or due to significant side effects
286
Q

What is pyridostigmine?

A

Anti cholinesterase inhibitor

287
Q

What is second and third line therapies for maintaining remission in MG?

A

Second line
 Azathioprine – slow working
 Mycophenolate
 Methotrexate

Third line
 Cyclosporin
 Rituximab

288
Q

What is the treatment of a myasthenia crisis?

A

o Intravenous immunoglobulin
o Maximise steroids
o Plasma exchange
o Ventilation

289
Q

Describe the prognosis of MG

A
  • Generally good but improvement takes months
  • Risk of iatrogenic side effects
  • 10% have brittle disease that can be very difficult to manage
290
Q

What is Guillain-barre syndrome?

A
  • It’s a neuropathy
  • Acute (rare for a neuropathy)
  • Usually demyelinating (and potentially treatable)
  • Acute inflammatory demyelinating polyneuropathy
291
Q

What is the presentation of GBS?

A
  • ¬Acute ascending symmetric weakness hour to days, at its worst by 4 weeks
  • Pain in 2/3rds
  • LMN ± mild sensory signs
  • Facial weakness ± other CN signs in ½
  • Respiratory weakness 1/3
  • Bulbar involvement ½
  • CVS instability 2/3
  • (Sphincter signs) – rare in GBS but can happen
292
Q

Describe lumbar puncture findings in GBS

A
  • First thing to become abnormal
    o Compared to NCS
  • CSF: Usually <5 WCC, protein <0.45 g/L, glucose >2/3rds blood concentration
  • In GBS – protein elevated but normal cells
293
Q

Describe NCS findings in GBS

A
  • F wave first to become abnormal in an NCS

- Test of the conduction of the most proximal part of the nerve

294
Q

Describe the pathology of GBS

A
  • “Friendly fire”
  • T-cells mistakenly identify myelin epitopes as foreign “molecular mimicry”
  • Both cellular and humoral mechanisms
  • Interleukon-2 and TNF may be involved
  • Cytokine attract macrophages attack myelin
  • Complement-fixing anti-myelin antibodies are present
  • Ganglioside antibodies – attack axons
295
Q

How is the diagnosis of GBS made?

A
  • What is it?
    o Clinical
    o Lumbar puncture
    o NCS after first week (can be normal, or delayed F waves) – can inform progress
  • What isn’t it?
    o Consider MRI to exclude acute cord lesion
  • What is complicating it?
    o Measure FVC
    o ECG
  • What’s the antibody?
    o Ganglioside antibodies (special circumstances)
296
Q

What is a GBS chameleon?

A

A condition that is GBS but doesn’t look like it - it presents atypically

297
Q

Name some GBS chameleons

A
  • AMAN etc
  • Miller-fisher syndrome
  • Bickerstaff’s
  • Pharyngeal-cervical-brachial
  • Paraparetic
298
Q

What two types of complications can you get in GBS?

A
  • Respiratory

- Cardiac

299
Q

Describe the treatment of GBS

A

Intravenous immunoglobulin or plasmapheresis if unable to walk
o Most people

Best supportive care
o Respiratory support in 1/3
o Arrhythmias
o NG feeding

Prevent/treat secondary complications
o LMWH, infections, pain etc

300
Q

Are steroids effective in GBS?

A

Steroids ineffective

o (GBS steroid trial group. Lancet 1993)

301
Q

Describe the prognosis of GBS

A
  • Most patients fully recover - >60% but can take up to 18 months
  • Death <5%
  • Residual disability
  • Poor prognostic factors – age, diarrhoea, weak arms (time to max disability?)
  • Recurrent GBS 2-5% - does this exist?
302
Q

What is CIDP?

A
  • Chronic inflammatory demyelinating neuropathy

- It’s demyelinating not axonal (potentially treatable)

303
Q

Describe the classical CIDP patient

A
  • Like GBS but slower
  • Like GBS but relapses
  • Behaves more like a normal neuropathy
  • Not usually prodrome or the dramatic respiratory failure
  • LMN signs
  • LP high protein, NCS demyelination
  • Treatable with immunosuppressants
304
Q

What is the different definitions of GBS and CIDP?

A
  • Guillain-Barre syndrome progresses to nadir in <4weeks
  • CID progresses to nadir in >8 weeks
  • Between 4 and 8 weeks = Subacute inflammatory demyelinating polyneuropathy

A spectrum?

305
Q

Describe the presentation of CIDP

A
  • Slowly progressive – at least 8 weeks to nadir in 2/3
  • Relapsing in 1/3
  • Can present acutely
  • Symmetrical or asymmetrical
  • Gait problems
  • ICP headaches
  • LMN signs as in GBS
  • Large fibre sensory signs more frequent
  • Bulbar symptoms less frequent
  • Facial weakness and ophthalmoparesis can occur
  • Autonomic symptoms and respiratory weakness can occur
  • Can rarely be fatal
  • Many variants
306
Q

Describe investigations of CIDP

A
  • Similar to GBS
  • Look for alternative causes of demyelinating neuropathy
    o Paraproteins
    o Inherited
    o Drugs
    o HIV
  • NCS more useful
  • Antibodies can be useful in variants (e.g. anti-MAG)
  • Consider CMT genetics
  • Rarely nerve biopsy
307
Q

What is the treatment for for CIDP?

A
  • Evidence for steroids (Pred 60, or pulsed dex, van Schaik et al, Lancet neurol 2012)
  • Steroid-sparing agents may be used (azathioprine, mycophenolate, methotrexate, cyclophosphamide, cyclosporin)
  • IV immunoglobulin, PE
308
Q

Describe the prognosis of CIDP

A
  • Relapsing better than progressive?
  • 70% recover well from relapses
  • 90% respond to treatment initially, 70% sustained
  • Mortality
  • Chronic disease
  • Much is unknown
309
Q

Describe the pathophysiology of CIDP

A
  • Precise mechanism unknown
  • Cellular and humoral mechanisms
  • Perivascular inflammation with macrophages and lymphocytes
  • Evidence of chronic demyelination/remyelination on biopsies
    o Onion bulbs
310
Q

What are the presenting features of vasculitis of the CNS?

A
  • Based on 70 consecutive neurology cases
  • Systemically unwell (57%)
  • Headache (46%)
  • Stroke like episodes (41%)
  • Additional organ involvement (27%)
  • Mononeuropathy multiplex (17%)
  • Cranial nerve palsies (11%)
  • Seizures (11%)
  • Purely cognitive (5%)
  • Muscle involvement (3%)
311
Q

What are some common neurological presenting features of vasculitis?

A
  • Headaches
  • Stroke like episodes/focal neurological deficit
  • Encephalopathic
    o Confusion, agitation, decreased level of consciousness
  • Foot drop/asymmetric neuropathy
312
Q

Name some types of vasculitis

A
  • Based on 70 neurology cases
  • Isolated to CNS (26%)
  • Giant cell arteritis (23%)
  • Wegener’s spectrum (18%)
  • Associated with CTD (11%)
  • Isolated pachymeningitis (6%)
  • Churg Strauss (5%)
  • Isolated to PNS (3%)
  • PAN (2%)
  • Takayasu’s’ (2%)
313
Q

Name some differential diagnoses of vasculitis

A
  • CNS infection
    o HSE, TB, viral encephalitis, HIV
  • CNS malignancy
    o Malignant meningitis, lymphomas
  • Venous sinus thrombosis
  • Subarachnoid haemorrhage/vasospasm
  • Embolic strokes due to SBE
  • Reversible cerebral vasoconstriction
314
Q

What are some secondary causes of CNS vasculitis?

A
  • HIV, Varicella zoster, TB, syphilis, Hep C
  • In association with malignancies
  • In association with connective tissue diseases
315
Q

What would find on blood tests of someone with CNS vasculitis?

A
  • Raised inflammatory markers at baseline
  • ESR (80%)
  • CRP (70%)
  • Low albumin (57%)
  • High platelet count (46%)
  • But up to 20% - no abnormalities
316
Q

What immunology results would you find in a CNS vasculitis patient?

A
  • One or more abnormalities in <50%
  • Rheumatoid factor
  • P or C ANCA
  • Lots of patients have MGUS
    o Monoclonal gammopathy of underdetermined significance
    o Asymptomatic
    o Premalignant condition
317
Q

What would find on a LP in a patient with CNS vasculitis?

A
  • Abnormal in up to 80% of patients with CNS vasculitis
  • Raised protein most common (50%)
  • Lymphocytes (25%)
  • OCBs (20%)
  • Matched bands (25%)
  • Blood (15%)
318
Q

What general observations can be made about imaging in CNS vasculitis?

A
  • If the MRI scan is normal it is highly unlikely that the patient has CNS vasculitis
    o 100% sensitivity in biopsy proven cases
  • MRI usually normal in GCA at presentation
  • Imaging the arteries (MRA, CTA, 4 vessel angiogram) can be helpful but an abnormal result does not diagnose CNS vasculitis
  • DWI can be helpful in dating vasculitic strokes
319
Q

Describe the evidence surrounding MRI vs angiogram in CNS vasculitis

A
  • 18 patients with biopsy proven CNS vasculitis
  • All had abnormal MRI
  • Only 65% have abnormal angiograms
    (Pomper et al, AJNR, 1999)
  • In other series the sensitivity of angiograms was as low as 20%
  • Angiograms not helpful in small vessel vasculitis
320
Q

When should a patients with suspected vasculitis receive a brain biopsy?

A
  • In patients with suspected primary angiitis of the CNS but with inconclusive imaging
321
Q

What is the sensitivity and safety of brain biopsies?

A
  • Sensitivity is somewhere between 53-74%, but can be increased to over 80% by targeting areas of imaging abnormalities
  • Not always positive but may reveal different underlying cause on further examination
  • Relatively safe and effective
    o (Beuker et al, Therapeutic advances in neurological disorders, 2018)
322
Q

What are some precipitant factors of reversible cerebral vasoconstriction syndrome?

A

o Drugs e.g. cannabis, cocaine, amphetamines but also ergotamine, SSRI, IVIgs
o Pregnancy and puerperium
o Idiopathic

323
Q

What are some distinguishing features of reversible cerebral vasoconstriction syndrome

A 
o	Female predominance
o	Acute onset of headache (mimics SAH)
o	Usually no prodromal illness
o	Usually no focal neurology 
o	Abnormal angiogram or CTA or MRA
o	Usually normal MRI but may have cortical SAH, intracerebral bleed, or CVA
324
Q

What did Ducros et al study?

A

67 consecutive cases of cerebral vasoconstriction syndrome over 3 years

o	Spontaneous in 37% 
o	Cannabis use in 32%
o	SSRI use in 21% 
o	Postpartum in 12%
o	Cortical SAH in 22%
o	Intracerebral haemorrhage in 6%
o	Angiograms normal by 3 months 
 (Brain, 2007)
325
Q

What is better for monitoring CNS vasculitis - MRI vs Angiogram?

A
  • Some angiographic changes in vasculitis are permanent so not good for monitoring
  • May be useful in reversible cerebral vasoconstriction syndrome as by definition angiography becomes normal by 3 months (without any treatment)
  • MRI much more sensitive but beware of timing or MRI vs clinical state of patient
326
Q

What is the treatment of CNS vasculitis?

A
  • Should be tailored to each case
  • Cyclophosphamide is not always essential
  • Adjust frequency of pulses according to patient’s clinical state
  • Avoid using steroids for too long
  • Mycophenolate seem the best choice for maintaining remission
  • Rituximab for resistant cases
327
Q

Describe the cerebellum

A
  • The little brain
  • The number of neurons in the cerebellum (100 billion) exceeds the total number in the remaining parts of the brain
  • Contains complete motor and sensory representation of the whole body
  • Controls the timing and pattern of motor activation during movement
  • Dysfunction causes ataxia (Greek for lack of order)
328
Q

What are the outputs of the cerebellum?

A

Purkinje cells are the only output

329
Q

What are some symptoms of cerebellar dysfunction?

A
  • Slurring of speech (staccato speech)
  • Oscillopsia (not very common) - Sensation that the surrounding environment is moving when it is not
  • Clumsiness (arms and legs)
  • Loss of precision of movement
  • Intention tremor
  • Unsteadiness when walking
  • Falls
  • Unsteadiness worse in the dark
  • Cognitive problems
330
Q

What are the signs of cerebellar dysfunction?

A
  • Gait ataxia
  • Truncal ataxia
  • Limb ataxia
  • Action tremor
  • Dysdiadochokinesia
  • Nystagmus
  • Dysarthria
331
Q

What are the classifications of ataxias?

A
  • Congenital ataxias E.g. cerebellar dysgenesis
  • Diseases where ataxia is one of many features - Usually autosomal recessive disorders
  • Episodic ataxias (e.g. EA1, 2)
  • Autosomal recessive ataxias (e.g. FA)
  • Autosomal dominant ataxias (SCAs)
  • Sporadic ataxias (e.g. MSA-C, gluten ataxia)
332
Q

What ataxias are not included in the classification?

A

Ataxias due to structural damage are not included in the classification

333
Q

What things would you include in an ataxia history?

A 
o	Age of onset
o	Rate of progression 
o	Additional features (genito-urinary, postural)
o	Pattern of involvement 
o	Detailed family history 
o	Alcohol intake
o	Exposure to drugs toxic to cerebellum
334
Q

What would you include in an ataxia examination?

A

o Eye involvement (nystagmus, broken pursuit)
o Limb ataxia
o Gait ataxia
o Symmetrical vs unilateral
o Evidence of peripheral neuropathy or sensory
o Neuronopathy (e.g. sensory ataxia)
o Evidence of postural blood pressure fall

335
Q

What does imaging with MRI exclude in ataxia?

A

 Cerebrovascular damage (posterior circulation stroke)
 Primary tumours
 Secondary tumours
 Hydrocephalus
 MS (Primary progressive)
 White matter involvement in leukodystrophy
 Cerebellar dysgenesis/malformations

336
Q

What is the most common causes of sporadic ataxia? Include evidence

A

idiopathic sporadic ataxia

Sheffield ataxia clinic 1996-2010, total of 640 patients assessed

337
Q

Name some causes of sporadic ataxia

A
  • Most common – idiopathic sporadic ataxia
  • Gluten ataxia
  • Clinically probable MSA-C
  • Genetic diagnosis
  • Alcohol related
  • Paraneoplastic ataxia
  • Anti-GAD associated ataxia
  • Least common – opsoclonus myoclonus
338
Q

Define gluten sensitivity

A

A state of heightened immunological responsiveness to ingested gluten in genetically susceptible individuals (Marsh 1995)

339
Q

Do you have to enteropathy to gluten sensitive?

A

No

Spectrum of mucosal damage ranges from normal to hypoplastic atrophic (Marsh Scanning Mricrosc, 1988)

340
Q

What are the neurological manifestations of gluten sensitivity? (From 694 patients seen in gluten/neurology clinic 1994-2014)

A
  • Ataxia most common
  • Peripheral neuropathy
    o Sensorimotor axonal neuropathy
    o Sensory ganglionopathy
  • Encephalopathy
  • Myoclonic ataxia (hyperexcitable brain)
  • Less common manifestations
    o Myopathy, myelopathy, epilepsy, chorea, migratory neuritis, stiff person syndrome
341
Q

What is gluten ataxia?

A
  • Sporadic idiopathic ataxia but some familial cases described
  • Presence of serological markers of sensitivity to gluten
342
Q

Describe the prevalence of gluten ataxia

A

Based on antigliadin antibodies

o 15% of all ataxias
o 42% of all idiopathic sporadic ataxias
o 12% of genetically characterised ataxias
o 12% in healthy controls

343
Q

What is the treatment of gluten ataxia?

A

Dietary treatment

o Improvement of ataxia within a year of strict gluten free diet even in those patients without enteropathy
o (Hadjivassiliou et al, J Neurol Neurosurg Psychiatry, 2003)

344
Q

Describe gluten neuropathy

A
  • Symmetrical sensorimotor length dependent neuropathy
  • Accounts for 26% of all neuropathies and 34% of idiopathic neuropathies
  • Neuropathy was found in 21% of patients with known coeliac disease on gluten free diet
345
Q

What is the effect of a gluten free diet on gluten neuropathy?

A

o Neurophysiological evidence of improvement of the neuropathy within a year of adherence to a strict gluten free diet
o Irrespective of the presence of enteropathy
o (Hadjivassiliou et al, Dietary treatment of gluten neuropathy, Muscle and Nerve 2006)

346
Q

Describe gluten encephalopathy

A
  • Episodic often severe and intractable headaches rarely with focal deficits
  • White matter abnormalities on MRI
  • Headache improves on gluten free diet; the white matter changes do not progress but do not resolve either
347
Q

What did neurological examination of established coeliac patients show?

A
  • Study on 33 consecutive patients with established CD
  • All patients underwent neurological examination and brain imaging
  • Abnormal cerebellar MR spectroscopy in over 50%
  • Significantly less cerebellar volume when compared to controls
348
Q

What a did a 3 year prospective study of newly diagnosed coeliac patients show>

A
  • All patients underwent neurological examination followed by brain imaging
  • 100 consecutive patients
  • 61% had neurological symptoms
    o 45% headache, 26% balance, 14% sensory
  • 42% had evidence of neurological dysfunction on clinical examination
    o 38% evidence of cerebellar dysfunction including 9 with nystagmus, 5% sensory signs and 1 had myoclonus
  • Imaging
    o 44% had abnormal MR spectroscopy of the cerebellum (3% controls)
    o 56% of patients with abnormal MRs had clinical evidence of balance problems
349
Q

What are the differences between CD patients presenting with ataxia vs GI symptoms?

A
  • Patients presenting with neurological symptoms are likely to be diagnosed with CD much later (61 vs 47 years)
  • They are neurologically more severely affected at the time of presentation (clinical and imaging)
  • Diet has a stabilising effect, but they remain disabled if they had the ataxia for many years
350
Q

Why might a patient with classical GI presentation of GI may have less neurological deficit?

A

Patients with the classical GI presentation have the advantage of early diagnosis and thus prevention of extraintestinal manifestations

351
Q

Define non-coeliac gluten sensitivity

A

Patients who benefit (GI or neurological symptoms) from a gluten free diet in the absence of enteropathy

352
Q

What proportion of gluten neurology patients have gluten enteropathy on biopsy?

A
  • Only 41% of the neurology patients have enteropathy on biopsy
  • 37% no enteropathy but have the HLA DQ2 or DQ8 (potential CD)
  • 22% no enteropathy and HLA other than DQ2/DQ8

Distribution of ataxia in the 3 groups was similar

353
Q

What is the autoantigen in CD?

A

Transglutaminase 2

354
Q

What is the autoantigen in dermatitis herpetiformis?

A

TG3

355
Q

What is thought to be the autoantigen in gluten ataxia?

A

TG6

o 73% of patients with positive antigliadin antibodies and ataxia were also positive for TG6
o 40% of UK patients with newly diagnosed CD were positive for anti-TG6 but only 14% in a Finish cohort of patients with CD

356
Q

What is the role of semicircular canals?

A

o Provide sensory input about head velocity

o Enables vestibula-ocular (VOR) to generate eye movements that matches the velocity of the head movement

357
Q

What is the role of otolith organs?

A

o Register forces related to linear acceleration
o Utricle – horizontal translation with constant centre of gravity
o Saccule – vertical translation with shifting centre of gravity

358
Q

What reflexes does the balance system generate?

A
  • Both generate the vestibulospinal reflex and the vestibulocollic reflex
359
Q

What components (other than the vestibule) make up the balance system?

A

o Processing of balance perception is a central process
o Starts from the vestibular nerve
o Is a complex interplay between the optical system, the proprioceptive system, the motor system and the cognitive centres

360
Q

What is the functions of the balance system?

A
  • Maintains posture

- Produces kinetic contractions to generate ocular stability and helps maintain muscle tone

361
Q

What is the main principles of assessing the balance system?

A
  • Distinguish between central and peripheral causes of imbalance
  • Formulation of effective management regimen including compensation, adaptation and habituation protocols with customised rehabilitation exercises
  • Particle repositioning manoeuvres
  • Exclusion/inclusion of vestibular pathology in solitary/multifactorial conditions
362
Q

What should be included in a balance history?

A 
Different presentations
Type - vertigo or otherwise
Duration 
LOC
Trigger 
Postural instability 
Visual vertigo
363
Q

What are the difference presentations of balance disorders?

A 
o	Episodic 
o	Sustained 
o	Visual vertigo 
o	Positional 
o	Oscillopsia 
o	Hearing 
o	Central symptoms/ataxia
o	Headache 
o	Postural instability
364
Q

What does an episodic presentation of a balance disorder suggest?

A

Vestibular pathology

365
Q

What does loss of consciousness in a balance disorder suggest?

A

Non-vestibular pathology

366
Q

What triggers are suggestive of vestibular pathology?

A

Movement, aural pressure changes and darkness induced

367
Q

What suggests postural hypotension as a cause of a balance disorder?

A

Triggered by movement from dependent position

368
Q

What is a headache in a balance disorder suggestive of?

A

Suggestive of migraine variant

369
Q

What is postural instability in a balance disorder suggestive of?

A

Suggestive of TIA or central syndromes

370
Q

How are the semi-circular canals examined?

A 
o	Nystagmus 
o	Head impulse test
o	Provocation tests
o	Head shake test
o	Dynamic visual acuity
371
Q

How is the CNS examined in balance disorders?

A

o Non-vestibular nystagmus
o Pursuits and saccades
o VOR cancel

372
Q

How are otolith organs examined?

A

o Head heave test
o Subjective visual vertical
o Ocular counter rolling
o Skew deviation

373
Q

What are the vestibulo spinal/cervical tests?

A 
o	Romberg tests
o	Unterberger and Fukuda – Stepping on spot with eyes closed
o	Quix and Barany tests 
o	Gait tests
o	Lateral flexion
374
Q

What are the characteristics of vestibular nystagmus?

A
  • Usually horizontal with fast and a quick phase
  • May have a latent period
  • Sustained by does not change direction on gaze eccentricities and may fatigue after some time
  • Follows Alexander’s law
    o Nystagmus is increased with the eyes directed to the fast phase direction
    o E.g. down in a downbeat nystagmus
  • Abolished or decreased by optic fixation
  • Does not rebound on spontaneous gaze
  • Any nystagmus or eye movement which does not follow the above may be central
375
Q

What are the investigations of balance disorders?

A
  • Pure Tone Audiometry (PTA), Tympanometry and Otoacoustic Emissions (OAE)
    o To assess the function of the ear
  • Quantification of vestibular hypofunction – Videonystagmography
    o Nystagmus
    o Dix Hallpike test – to exclude BPPV
    o Caloric tests – tests function of lateral semi-circular canals
    o Smooth pursuit and saccades
  • Rotatory chair tests and video head impulse test (vHIT)
  • Dynamic posturography for assessing central sensory organisation
    o Also useful for prognosis
  • Subjective visual vertical and Visual evoked myogenic potential (VEMP)
    o Assesses otolith function
  • Imaging studies – CT, MRI, Doppler
  • Blood tests when indicated
376
Q

What can cause the decompensation or manifestation of balance disorders?

A
  • Poor eye/head stabilisation
  • Inadequate/inappropriate CNS activity
  • Psychological dysfunction/age
  • Medicines/illness
  • Inadequate/impaired musculoskeletal activity
  • Impaired/inappropriate CNS balance strategies
  • Impaired sensory inputs
  • Fluctuating vestibular activity
  • Disordered perception of stability
377
Q

Describe the epidemiology of balance disorders

A
  • 17% at all ages, 40% from 60yrs
  • 26% are disabled
  • 40% are otological
  • 33% of falls due to peripheral vestibular problem
378
Q

Name the 5 major subtypes of peripheral vestibular disorders

A
  • Acute vestibular event
    o Infection or vascular
  • Intermittent decompensation following acute event
    o Traumatic fibrosis, tumour, space occupying lesion
  • Paroxysmal irritation of the vestibular system
    o BPPV, endolymphatic hydrops, vestibular paroxysmia, cervical causes
  • Mal De Debarquement (MDD) like syndrome and visual vertigo
  • Bilateral vestibular failure
379
Q

Name some causes of peripheral vestibular disorders

A
  • Inflammation
  • Trauma
  • Infection
  • Tumour
  • Idiopathic
  • Degeneration
  • Ototoxic
  • Others – e.g. hyperviscosity, anaemia, metabolic
380
Q

What is the relative prevalence of different peripheral vestibular disorders according to Brandt and Strupp 2004

A
  • Benign paroxysmal positioning vertigo (18.3%)
  • Phobic postural vertigo (PPV) (15.9%)
  • Vestibular migraine (9.6%)
  • Vestibular neuritis (7.9%)
  • Meniere’s disease (7.8%)
  • Bilateral vestibulopathy (3.6%)
  • Psychogenic vertigo (3.6%)
  • Vestibular paroxysmia (2.9%)
381
Q

What is an acute vestibular event?

A

infection, inflammatory, vascular or SOL – sudden onset lasting for days followed by intermittent and episodic if decompensated

o Includes neuritis, labyrinthitis and TIA

382
Q

Describe BPPV

A

Sudden onset, intermittent, positional lasting few seconds, recurrent and 7 types

383
Q

Describe endolymphatic hydrops

A

sudden onset lasting for minutes to days, fluctuating with audiological features

384
Q

Describe vestibular paroxysmia

A

sudden and pole axing lasting for few seconds, due to vestibular neuralgia as a result of compression in cerebellar pontine angle

385
Q

What is migraine variant vertigo?

A

migrainous features with dizziness lasting for minutes to hours with other autonomic features

386
Q

What is Mal de Debarquement?

A

sensation of rocking after travel, possible otolith related

387
Q

What are the clinical features of central vestibular/balance disorders?

A
  • Chronic non episodic dizziness as difficult decompensation
  • Alleviated on eye closure
  • Neurological signs and central derangements of VOR control
  • Ataxia or movement disorders including tremors
  • May show signs of peripheral vestibular insufficiency in AICA infarction
  • Diagnosis by imaging and specific blood markers if indicated
  • Treatment of cause and physiotherapy
    o Vestibular physiotherapy effective in 30%
388
Q

What is psychogenic vertigo?

A
  • With or without overt vestibular or central illness
  • Associated with somatisation
  • Continuous feeling of dizziness
  • Includes phobic postural vertigo and anxiety related vertigo
  • Treated by management of psychiatric condition if any, stress and relaxation exercises and CBT
389
Q

What are the management principles of balance disorders?

A
  • Treatment of active or acute condition with anti-labyrinthine medication or anti migraine therapy
  • Carbamazepine for vestibular neuralgia
  • Customised vestibular and frequency and site-specific rehabilitation
  • Particle repositioning for BPPV
  • Treatment for cause for decompensation
  • Surgery for space occupying lesions, vestibular paroxysmia
  • Stress management and CBT
390
Q

What is the current state of management of balance disorders?

A
  • Paucity of dedicated vestibular services with limited access to integrated MDT
  • Referrals primarily directed to specialities with general training in vestibular sciences
  • Unavailability of dedicated medical expertise to patients presenting in a general service
  • An average of 4.5 physician visits per patient before receiving correct diagnosis
  • Cost of delay is significant – circa £2000 per patient
  • (Data from RCP London)

Clinical Neurology (3 decks)

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